STAT3 inhibition suppresses hepatic stellate cell fibrogenesis

HJC0123, a potential therapeutic agent for liver fibrosis

Omar Nunez Lopez, Fredrick J. Bohanon, Xiaofu Wang, Na Ye, Tiziana Gorgun, Yesenia Rojas-Khalil, Haijun Chen, Haiying Chen, Jia Zhou, Ravi Radhakrishnan

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Hepatic Stellate Cells (HSCs) are the major source of the excessive extracellular matrix (ECM) production that replaces liver parenchyma with fibrous tissue during liver fibrosis. The signal transducer and activator of transcription 3 (STAT3) promotes HCSs survival, proliferation, and activation contributing to fibrogenesis. We have previously used a fragment-based drug design approach and have discovered a novel STAT3 inhibitor, HJC0123. Here, we explored the biological effects of HJC0123 on the fibrogenic properties of HSCs. HJC0123 treatment resulted in the inhibition of HSCs proliferation at submicromolar concentrations. HJC0123 reduced the phosphorylation, nuclear translocation, and transcriptional activity of STAT3. It decreased the expression of STAT3-regulated proteins, induced cell cycle arrest, promoted apoptosis and downregulated SOCS3. HJC0123 treatment inhibited HSCs activation and downregulated ECM protein fibronectin and type I collagen expression. In addition, HJC0123 increased IL-6 production and decreased TGF-β induced Smad2/3 phosphorylation. These results demonstrate that HJC0123 represents a novel STAT3 inhibitor that suppresses the fibrogenic properties of HSCs, suggesting its therapeutic potential in liver fibrosis.

Original languageEnglish (US)
Pages (from-to)100652-100663
Number of pages12
JournalRSC Advances
Volume6
Issue number102
DOIs
StatePublished - 2016

Fingerprint

STAT3 Transcription Factor
Transcription
Liver
Transducers
Phosphorylation
Chemical activation
Proteins
Cell proliferation
Cell death
Collagen
Extracellular Matrix Proteins
Cells
Collagen Type I
Hepatic Stellate Cells
2-phenylquinoline-4-carboxylic acid (1,1-dioxo-1H-1lambda6-benzo(b)thiophen-6-yl)amide
Fibronectins
Tissue
Interleukin-6
Apoptosis
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

STAT3 inhibition suppresses hepatic stellate cell fibrogenesis : HJC0123, a potential therapeutic agent for liver fibrosis. / Lopez, Omar Nunez; Bohanon, Fredrick J.; Wang, Xiaofu; Ye, Na; Gorgun, Tiziana; Rojas-Khalil, Yesenia; Chen, Haijun; Chen, Haiying; Zhou, Jia; Radhakrishnan, Ravi.

In: RSC Advances, Vol. 6, No. 102, 2016, p. 100652-100663.

Research output: Contribution to journalArticle

Lopez, Omar Nunez ; Bohanon, Fredrick J. ; Wang, Xiaofu ; Ye, Na ; Gorgun, Tiziana ; Rojas-Khalil, Yesenia ; Chen, Haijun ; Chen, Haiying ; Zhou, Jia ; Radhakrishnan, Ravi. / STAT3 inhibition suppresses hepatic stellate cell fibrogenesis : HJC0123, a potential therapeutic agent for liver fibrosis. In: RSC Advances. 2016 ; Vol. 6, No. 102. pp. 100652-100663.
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